Identifying novel biological activities of FDA-approved drugs has emerged as a viable strategy to expedite the drug discovery process. The pharmacokinetic and toxicological profiles of these compounds are well-understood and they are inherently “drug-like.” To this end, drug development researchers have made a concerted effort to incorporate small molecule libraries containing approved drugs in their high-throughput screens. Recently, two such screens designed to repurpose FDA-approved compounds as anti-cancer chemotherapeutics identified the clinically efficacious antifungal itraconazole (ITZ) as both an inhibitor of the hedgehog (Hh) signaling pathway (IC50=690 nM) and angiogenesis (IC50=160 nM
The Hh pathway is a developmental signaling pathway that plays a key role in directing growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors; most notably, basal cell carcinoma (BCC) and medulloblastoma (MB). Recent years have seen the development of numerous small molecule Hh pathway inhibitors, the majority of which directly bind Smoothened (SMO), a 7-transmembrane GPCR-like receptor and key regulator of pathway signaling. The most advanced of these compounds, the small molecule GDC-0449 (Vismodegib/Erivedge™), was approved by the FDA for the treatment of metastatic BCC, highlighting the clinical relevance of Hh pathway inhibition. The importance of angiogenesis in tumor formation, growth, and metastasis is well-documented and numerous small molecules and biologics that inhibit angiogenesis are clinically useful anti-cancer agents.
While itraconazole has anti-cancer activity, it can have serious detrimental interactions with other commonly taken medications such as anticoagulants, statins and calcium channel blockers. It is thus desirable to provide alternatives to itraconazole that maintain the anti-cancer properties, but that potentially do not have the side-effects observed for itraconazole.